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Fulltext Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, et al.

Nat Genet, 2016 Apr;48(4):374-86.
PMID: 26928228 DOI: 10.1038/ng.3521

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Fulltext Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Darabi H, Beesley J, Droit A, Kar S, Nord S, Moradi Marjaneh M, et al.

Sci Rep, 2016 Sep 07;6:32512.
PMID: 27600471 DOI: 10.1038/srep32512

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS

Park YH, Senkus-Konefka E, Im SA, Pentheroudakis G, Saji S, Gupta S, et al.

Ann Oncol, 2020 04;31(4):451-469.
PMID: 32081575 DOI: 10.1016/j.annonc.2020.01.008

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.
Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study

Bhoo-Pathy N, Verkooijen HM, Wong FY, Pignol JP, Kwong A, Tan EY, et al.

Int J Cancer, 2015 Nov 15;137(10):2504-12.
PMID: 26018878 DOI: 10.1002/ijc.29617

The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0-94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.
Fulltext Effect of ethnicity and socioeconomic variation to the gut microbiota composition among pre-adolescent in Malaysia

Chong CW, Ahmad AF, Lim YA, Teh CS, Yap IK, Lee SC, et al.

Sci Rep, 2015;5:13338.
PMID: 26290472 DOI: 10.1038/srep13338

Gut microbiota plays an important role in mammalian host metabolism and physiological functions. The functions are particularly important in young children where rapid mental and physical developments are taking place. Nevertheless, little is known about the gut microbiome and the factors that contribute to microbial variation in the gut of South East Asian children. Here, we compared the gut bacterial richness and composition of pre-adolescence in Northern Malaysia. Our subjects covered three distinct ethnic groups with relatively narrow range of socioeconomic discrepancy. These included the Malays (n = 24), Chinese (n = 17) and the Orang Asli (indigenous) (n = 20). Our results suggested a strong ethnicity and socioeconomic-linked bacterial diversity. Highest bacterial diversity was detected from the economically deprived indigenous children while the lowest diversity was recorded from the relatively wealthy Chinese children. In addition, predicted functional metagenome profiling suggested an over-representation of pathways pertinent to bacterial colonisation and chemotaxis in the former while the latter exhibited enriched gene pathways related to sugar metabolism.
Fulltext Prevalence and risk factors of intestinal parasitism among two indigenous sub-ethnic groups in Peninsular Malaysia

Chin YT, Lim YA, Chong CW, Teh CS, Yap IK, Lee SC, et al.

Infect Dis Poverty, 2016;5(1):77.
PMID: 27430215 DOI: 10.1186/s40249-016-0168-z

Intestinal parasitic infections (IPIs) among indigenous people have been widely documented in Malaysia, however, the prevalence of these infections remains high. In the past, most studies have focused on specific species of parasites but polyparasitism has received limited attention. In addition, epidemiology studies on indigenous people tend to consider them as a homogenous group, whereas in reality different sub-ethnic groups have different cultural and living practices. Variations in living habits such as personal hygiene practices may predispose different groups to different parasitic infections. To better understand prevalence and risk factors of intestinal parasitism among different sub-ethnic groups, the present study was conducted among two sub-ethnic groups of indigenous people (Temuan and Mah Meri) residing in Selangor state, Malaysia.
Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients

Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, et al.

Cancer Sci, 2007 Sep;98(9):1461-7.
PMID: 17627617

The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan-induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90-min intravenous infusion of 375 mg/m(2) once every 3 weeks (n = 45). Genotypic-phenotypic correlates showed a non-significant influence of UGT1A1*28 and ABCG2 c.421C>A polymorphisms on the pharmacokinetics of SN-38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN-38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC < or = 500/microL) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3-fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN-38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study.
Seroprevalence of Nipah Virus Infection in Peninsular Malaysia

Yong MY, Lee SC, Ngui R, Lim YA, Phipps ME, Chang LY

J Infect Dis, 2020 05 11;221(Suppl 4):S370-S374.
PMID: 32392323 DOI: 10.1093/infdis/jiaa085

Nipah virus (NiV) outbreak occurred in Malaysia in 1998. The natural host reservoir for NiV is Pteropus bats, which are commonly found throughout Malaysia. Humans become infected when NiV spills over from the reservoir species. In this study, NiV serosurveillance in Peninsular Malaysia, particularly among the indigenous population, was performed. The collected samples were tested for presence of NiV antibodies using a comparative indirect enzyme-linked immunosorbent assay based on the recombinant NiV nucleocapsid (rNiV-N) protein. We found that 10.73% of the participants recruited in this study had antibodies against rNiV-N, suggesting possible exposure to NiV.
Fulltext Helminth infection promotes colonization resistance via type 2 immunity

Ramanan D, Bowcutt R, Lee SC, Tang MS, Kurtz ZD, Ding Y, et al.

Science, 2016 Apr 29;352(6285):608-12.
PMID: 27080105 DOI: 10.1126/science.aaf3229

Increasing incidence of inflammatory bowel diseases, such as Crohn's disease, in developed nations is associated with changes to the microbial environment, such as decreased prevalence of helminth colonization and alterations to the gut microbiota. We find that helminth infection protects mice deficient in the Crohn's disease susceptibility gene Nod2 from intestinal abnormalities by inhibiting colonization by an inflammatory Bacteroides species. Resistance to Bacteroides colonization was dependent on type 2 immunity, which promoted the establishment of a protective microbiota enriched in Clostridiales. Additionally, we show that individuals from helminth-endemic regions harbor a similar protective microbiota and that deworming treatment reduced levels of Clostridiales and increased Bacteroidales. These results support a model of the hygiene hypothesis in which certain individuals are genetically susceptible to the consequences of a changing microbial environment.
Fulltext Clostridia isolated from helminth-colonized humans promote the life cycle of Trichuris species

Sargsian S, Chen Z, Lee SC, Robertson A, Thur RS, Sproch J, et al.

Cell Rep, 2022 Nov 29;41(9):111725.
PMID: 36450245 DOI: 10.1016/j.celrep.2022.111725

Soil-transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolate and sequence the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with a high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians confirm the prevalence of species corresponding to these isolates and reveal a specific association between Peptostreptococcaceae family members and helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli display superior capacity to promote the life cycle of whipworm species, including hatching of eggs from Trichuris muris and Trichuris trichiura. These findings support a model in which helminths select for gut colonization of microbes that support their life cycle.
Evidence for the Higgs Boson Decay to a Z Boson and a Photon at the LHC

Aad G, Abbott B, Abeling K, Abicht NJ, Abidi SH, Aboulhorma A, et al.

Phys Rev Lett, 2024 Jan 12;132(2):021803.
PMID: 38277607 DOI: 10.1103/PhysRevLett.132.021803

The first evidence for the Higgs boson decay to a Z boson and a photon is presented, with a statistical significance of 3.4 standard deviations. The result is derived from a combined analysis of the searches performed by the ATLAS and CMS Collaborations with proton-proton collision datasets collected at the CERN Large Hadron Collider (LHC) from 2015 to 2018. These correspond to integrated luminosities of around 140 fb^{-1} for each experiment, at a center-of-mass energy of 13 TeV. The measured signal yield is 2.2±0.7 times the standard model prediction, and agrees with the theoretical expectation within 1.9 standard deviations.
Validation of the CancerMath prognostic tool for breast cancer in Southeast Asia

Miao H, Hartman M, Verkooijen HM, Taib NA, Wong HS, Subramaniam S, et al.

BMC Cancer, 2016 10 21;16(1):820.
PMID: 27769212

BACKGROUND: CancerMath is a set of web-based prognostic tools which predict nodal status and survival up to 15 years after diagnosis of breast cancer. This study validated its performance in a Southeast Asian setting.
METHODS: Using Singapore Malaysia Hospital-Based Breast Cancer Registry, clinical information was retrieved from 7064 stage I to III breast cancer patients who were diagnosed between 1990 and 2011 and underwent surgery. Predicted and observed probabilities of positive nodes and survival were compared for each subgroup. Calibration was assessed by plotting observed value against predicted value for each decile of the predicted value. Discrimination was evaluated by area under a receiver operating characteristic curve (AUC) with 95 % confidence interval (CI).
RESULTS: The median predicted probability of positive lymph nodes is 40.6 % which was lower than the observed 43.6 % (95 % CI, 42.5 %-44.8 %). The calibration plot showed underestimation for most of the groups. The AUC was 0.71 (95 % CI, 0.70-0.72). Cancermath predicted and observed overall survival probabilities were 87.3 % vs 83.4 % at 5 years after diagnosis and 75.3 % vs 70.4 % at 10 years after diagnosis. The difference was smaller for patients from Singapore, patients diagnosed more recently and patients with favorable tumor characteristics. Calibration plot also illustrated overprediction of survival for patients with poor prognosis. The AUC for 5-year and 10-year overall survival was 0.77 (95 % CI: 0.75-0.79) and 0.74 (95 % CI: 0.71-0.76).
CONCLUSIONS: The discrimination and calibration of CancerMath were modest. The results suggest that clinical application of CancerMath should be limited to patients with better prognostic profile.
Observation of ϒ(2S)→γη_{b}(1S) Decay

Fulsom BG, Pedlar TK, Adachi I, Aihara H, Al Said S, Asner DM, et al.

Phys Rev Lett, 2018 Dec 07;121(23):232001.
PMID: 30576207 DOI: 10.1103/PhysRevLett.121.232001

We report the observation of ϒ(2S)→γη_{b}(1S) decay based on an analysis of the inclusive photon spectrum of 24.7 fb^{-1} of e^{+}e^{-} collisions at the ϒ(2S) center-of-mass energy collected with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We measure a branching fraction of B[ϒ(2S)→γη_{b}(1S)]=(6.1_{-0.7-0.6}^{+0.6+0.9})×10^{-4} and derive an η_{b}(1S) mass of 9394.8_{-3.1-2.7}^{+2.7+4.5} MeV/c^{2}, where the uncertainties are statistical and systematic, respectively. The significance of our measurement is greater than 7 standard deviations, constituting the first observation of this decay mode.
First Evidence for cos2β>0 and Resolution of the Cabibbo-Kobayashi-Maskawa Quark-Mixing Unitarity Triangle Ambiguity

Adachi I, Adye T, Ahmed H, Ahn JK, Aihara H, Akar S, et al.

Phys Rev Lett, 2018 Dec 28;121(26):261801.
PMID: 30636113 DOI: 10.1103/PhysRevLett.121.261801

We present first evidence that the cosine of the CP-violating weak phase 2β is positive, and hence exclude trigonometric multifold solutions of the Cabibbo-Kobayashi-Maskawa (CKM) Unitarity Triangle using a time-dependent Dalitz plot analysis of B^{0}→D^{(*)}h^{0} with D→K_{S}^{0}π^{+}π^{-} decays, where h^{0}∈{π^{0},η,ω} denotes a light unflavored and neutral hadron. The measurement is performed combining the final data sets of the BABAR and Belle experiments collected at the ϒ(4S) resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6}BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6}BB[over ¯] pairs recorded by the Belle detector. The results of the measurement are sin2β=0.80±0.14(stat)±0.06(syst)±0.03(model) and cos2β=0.91±0.22(stat)±0.09(syst)±0.07(model). The result for the direct measurement of the angle β of the CKM Unitarity Triangle is β=[22.5±4.4(stat)±1.2(syst)±0.6(model)]°. The measurement assumes no direct CP violation in B^{0}→D^{(*)}h^{0} decays. The quoted model uncertainties are due to the composition of the D^{0}→K_{S}^{0}π^{+}π^{-} decay amplitude model, which is newly established by performing a Dalitz plot amplitude analysis using a high-statistics e^{+}e^{-}→cc[over ¯] data sample. CP violation is observed in B^{0}→D^{(*)}h^{0} decays at the level of 5.1 standard deviations. The significance for cos2β>0 is 3.7 standard deviations. The trigonometric multifold solution π/2-β=(68.1±0.7)° is excluded at the level of 7.3 standard deviations. The measurement resolves an ambiguity in the determination of the apex of the CKM Unitarity Triangle.
First Measurements of Absolute Branching Fractions of the Ξ_{c}^{0} Baryon at Belle

Li YB, Shen CP, Yuan CZ, Adachi I, Aihara H, Al Said S, et al.

Phys Rev Lett, 2019 Mar 01;122(8):082001.
PMID: 30932568 DOI: 10.1103/PhysRevLett.122.082001

We present the first measurements of absolute branching fractions of Ξ_{c}^{0} decays into Ξ^{-}π^{+}, ΛK^{-}π^{+}, and pK^{-}K^{-}π^{+} final states. The measurements are made using a dataset comprising (772±11)×10^{6} BB[over ¯] pairs collected at the ϒ(4S) resonance with the Belle detector at the KEKB e^{+}e^{-} collider. We first measure the absolute branching fraction for B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0} using a missing-mass technique; the result is B(B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0})=(9.51±2.10±0.88)×10^{-4}. We subsequently measure the product branching fractions B(B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0})B(Ξ_{c}^{0}→Ξ^{-}π^{+}), B(B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0})B(Ξ_{c}^{0}→ΛK^{-}π^{+}), and B(B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0})B(Ξ_{c}^{0}→pK^{-}K^{-}π^{+}) with improved precision. Dividing these product branching fractions by the result for B^{-}→Λ[over ¯]_{c}^{-}Ξ_{c}^{0} yields the following branching fractions: B(Ξ_{c}^{0}→Ξ^{-}π^{+})=(1.80±0.50±0.14)%, B(Ξ_{c}^{0}→ΛK^{-}π^{+})=(1.17±0.37±0.09)%, and B(Ξ_{c}^{0}→pK^{-}K^{-}π^{+})=(0.58±0.23±0.05)%. For the above branching fractions, the first uncertainties are statistical and the second are systematic. Our result for B(Ξ_{c}^{0}→Ξ^{-}π^{+}) can be combined with Ξ_{c}^{0} branching fractions measured relative to Ξ_{c}^{0}→Ξ^{-}π^{+} to yield other absolute Ξ_{c}^{0} branching fractions.
Search for a Light CP-odd Higgs Boson and Low-Mass Dark Matter at the Belle Experiment

Seong IS, Vahsen SE, Adachi I, Aihara H, Al Said S, Asner DM, et al.

Phys Rev Lett, 2019 Jan 11;122(1):011801.
PMID: 31012694 DOI: 10.1103/PhysRevLett.122.011801

We report on the first Belle search for a light CP-odd Higgs boson, A^{0}, that decays into low mass dark matter, χ, in final states with a single photon and missing energy. We search for events produced via the dipion transition ϒ(2S)→ϒ(1S)π^{+}π^{-}, followed by the on-shell process ϒ(1S)→γA^{0} with A^{0}→χχ, or by the off-shell process ϒ(1S)→γχχ. Utilizing a data sample of 157.3×10^{6} ϒ(2S) decays, we find no evidence for a signal. We set limits on the branching fractions of such processes in the mass ranges M_{A^{0}}<8.97 GeV/c^{2} and M_{χ}<4.44 GeV/c^{2}. We then use the limits on the off-shell process to set competitive limits on WIMP-nucleon scattering in the WIMP mass range below 5 GeV/c^{2}.
Observation of ϒ(4S)→η^{'}ϒ(1S)

Guido E, Mussa R, Tamponi U, Aihara H, Al Said S, Asner DM, et al.

Phys Rev Lett, 2018 Aug 10;121(6):062001.
PMID: 30141661 DOI: 10.1103/PhysRevLett.121.062001

We report the first observation of the hadronic transition ϒ(4S)→η^{'}ϒ(1S), using 496 fb^{-1} data collected at the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We reconstruct the η^{'} meson through its decays to ρ^{0}γ and to π^{+}π^{-}η, with η→γγ. We measure B(ϒ(4S)→η^{'}ϒ(1S))=[3.43±0.88(stat)±0.21(syst)]×10^{-5}, with a significance of 5.7σ.
Observation of Transverse Λ/Λ[over ¯] Hyperon Polarization in e^{+}e^{-} Annihilation at Belle

Guan Y, Vossen A, Adachi I, Adamczyk K, Ahn JK, Aihara H, et al.

Phys Rev Lett, 2019 Feb 01;122(4):042001.
PMID: 30768311 DOI: 10.1103/PhysRevLett.122.042001

We report the first observation of the spontaneous polarization of Λ and Λ[over ¯] hyperons transverse to the production plane in e^{+}e^{-} annihilation, which is attributed to the effect arising from a polarizing fragmentation function. For inclusive Λ/Λ[over ¯] production, we also report results with subtracted feed-down contributions from Σ^{0} and charm. This measurement uses a dataset of 800.4 fb^{-1} collected by the Belle experiment at or near a center-of-mass energy of 10.58 GeV. We observe a significant polarization that rises with the fractional energy carried by the Λ/Λ[over ¯] hyperon.
Fulltext Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Orr N, Dudbridge F, Dryden N, Maguire S, Novo D, Perrakis E, et al.

Hum Mol Genet, 2015 May 15;24(10):2966-84.
PMID: 25652398 DOI: 10.1093/hmg/ddv035

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

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